xRead - An Update on Immunotherapy in Head and Neck Cancer (November 2025)

Clinical Review & Education Review

Immunotherapy in Head and Neck Squamous Cell Carcinoma

SCC who progressed on platinum-based chemotherapy, with a me dian OS of 8.4 months compared with 6.9 months in the standard care treatment group 24,25 ( Table1 ). For these phase 3 trials, the sur vival benefit of pembrolizumab therapy appeared to be greater in patients whose tumors expressed PD-L1. The survival benefit of pembrolizumab was noted irrespective of HPV status in CheckMate-141, 21 but on subgroup analysis in KEYNOTE-040, 23 pem brolizumab had no benefit in patients with HPV-related HNSCC. With meaningful response rates noted in the cetuximab- and platinum-refractory populations, additional trials aimed to evalu ate the efficacy of PD-1 ICIs as first-line treatment in patients with R/M HNSCC. In a randomized phase 3 study, KEYNOTE-048 24 was the first to demonstrate the efficacy and safety of pembrolizumab as first-line therapy. Subgroup analysis was performed using the com bined positive score (CPS), defined as the number of PD-L1– positive tumor cells, lymphocytes, and macrophages divided by the total number of tumor cells multiplied by 100. The trial demon strated improved survival with pembrolizumab as monotherapy in patients with a CPS of 1 or greater and as combination therapy with platinum and fluorouracil in all patients with R/M HNSCC who had not received previous systemic therapy for their R/M disease. 24 How ever, due to the logistical challenges of fluorouracil (continuous 4-day infusion, high administration costs) and its toxicity profile, KEYNOTE-B10 25 evaluated first-line pembrolizumab plus carbopla tin and paclitaxel instead of fluorouracil for R/M HNSCC. The study showed a 49% objective response rate with a manageable safety profile, thereby suggesting that combination first-line therapy of pembrolizumab plus platinum and paclitaxel instead of fluorouracil may be an alternative option for this patient population. 25 Following these landmark phase 3 trials, the FDA in 2016 ap proved nivolumab and pembrolizumab for patients with R/M HN SCC refractory to platinum-based chemotherapy regimens, and in 2019, the FDA approved first-line pembrolizumab in combination with platinum and fluorouracil for all patients with R/M HNSCC and pembrolizumab alone for patients with R/M HNSCC with a CPS of 1 or greater. 26 These indications remain the only FDA-approved ICI applications currently in HNSCC. Negative Phase 3 ICI Clinical Trials Building on the successes of these landmark trials, subsequent stud ies have aimed to further enhance survival in the R/M HNSCC setting. 27-33 These trials explored combining ICIs targeting both the CTLA-4 and PD-1/PD-L1 pathways, as this strategy has shown prom ise in other solid tumors, such as renal cell carcinoma. 34 Thephase 3EAGLE 27 and KESTREL 28 trials evaluated the efficacy of PD-L1 tar geting durvalumab either alone or in combination with tremelim umab, an ICI targeting CTLA-4. Both trials failed to show a signifi cant survival benefit with ICI monotherapy or combination therapy in platinum-refractory and first-line R/M HNSCC populations, re spectively ( Table2 ). 27,28 Based on these trials, many believe that ICIs targeting PD-L1 may be inferior to those targeting PD-1, although further evidence is needed to make any definitive conclusions. CheckMate-651, 29 a phase 3 randomized trial, also failed to show a benefit of first-line nivolumab plus ipilimumab, an ICI targeting CTLA-4, vs the EXTREME regimen (cetuximab plus cisplatin/ carboplatin plus fluorouracil 6 cycles, then cetuximab mainte

patient population. This narrative review discusses the landmark trials that have shaped the current landscape of HNSCC immuno therapy and the future directions that lie ahead.

Immune Checkpoints as Therapeutic Targets ICI therapy targets biologic checkpoints that attenuate natural im mune responses. 9 Through antibody-mediated blockade of im mune checkpoint receptors or their ligands, ICI therapy releases the molecular “brakes” of immune cells to trigger an antitumor response. 10 While the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) molecule was the first clinically targeted checkpoint, the inhibitory PD-1 and PD-L1 receptor-ligand interaction is now the dominant therapeutic target in immunotherapies across the onco logic spectrum. 11-13 T cell–specific upregulation of PD-1, driven by chronic antigen exposure in the tumor microenvironment, is part of an exhaustion program that attenuates T-cell antitumor function, leading to unabated tumor growth. 14 In addition, intrinsic or ac quired upregulation of PD-L1 on tumor cells complements T-cell PD-1 expression to inhibit antitumor responses. 15 Successful Landmark Trials Traditional approaches to patients with R/M HNSCC involve cyto toxic chemotherapies, including taxanes, platinum, and fluoroura cil. In 2006, the US Food and Drug Administration (FDA) approved the use of cetuximab, a monoclonal antibody directed at epider mal growth factor receptor, in combination with platinum-based chemotherapy and fluorouracil in the R/M setting. 16 The addition of cetuximab demonstrated improvements in survival (median OS of 7.4 months in the chemotherapy-only group vs 10.1 months in the chemotherapy with cetuximab group). Despite the promising im provements in survival, response rates were modest (36% in pa tients treated with cetuximab with chemotherapy). 16 To investigate more effective and less toxic treatment options in the platinum-refractory, second-line R/M HNSCC setting, ICIs tar geting PD-1 were first introduced in the KEYNOTE-012 17-19 and CheckMate-141 20,21 trials. KEYNOTE-012 17-19 was a phase 1b trial ad ministering pembrolizumab monotherapy to 60 patients with R/M PD-L1–positive HNSCC ( 1% of tumor or stromal cells expressing PD-L1 by immunohistochemistry) in its initial cohort and 132 biomarker-unselected patients with R/M HNSCC in its expansion co hort. KEYNOTE-012 showed an overall response rate of 18% on pooled analysis. 17-19 KEYNOTE-055, 22 a phase 2 trial, soon followed, recapitulating a meaningful clinical response rate of 16% in 171 treated patients who had both platinum and cetuximab exposure. CheckMate-141 20,21 was the first randomized phase 3 trial in R/M HN SCC that evaluated nivolumab, an ICI targeting PD-1, compared with investigator’s choice single-agent chemotherapy (methotrexate, do cetaxel, or cetuximab). The trial demonstrated a 13.3% response rate to nivolumab but an increase in median OS to 7.5 months com pared with 5.1 months in the standard care group. 20 Long-term 2-year follow-up demonstrated a sustained survival benefit for nivolumab vs investigator’s choice therapy (hazard ratio, 0.68; 95% CI, 0.54-0.86). 21 Similarly, a randomized phase 3 trial, KEYNOTE-040, 23 confirmed the efficacy of pembrolizumab in patients with R/M HN

522 JAMA Otolaryngology–Head & Neck Surgery May 2025 Volume 151, Number 5 (Reprinted)

jamaotolaryngology.com

© 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Downloaded from jamanetwork.com by Icahn School of Medicine at Mount Sinai user on 09/02/2025